Survival analysis of comprehensive treatment in Chinese patients with metastatic melanoma: A retrospective analysis

Abstract Background Most of the current progression of immune checkpoint inhibitors for malignant melanoma is based on data from Caucasians in Western countries, but the benefit of Chinese patients is limited, mainly due to different pathological subtypes. The patients in western countries are mainly skin melanoma (about 90%), while the acral and mucosal types are dominant in China, accounting for 41.8% and 22.6% respectively. Acral and mucosal melanoma have lower response rates to immunotherapy and chemotherapy. Objective Whether immune checkpoint inhibitors can improve the survival of Chinese patients with malignant melanoma, therefore, we conducted a retrospective analysis. Methods We analyzed 53 patients with metastatic melanoma treated in our hospital to evaluate the efficacy and safety of PD‐1 mAb in Chinese patients with metastatic melanoma, and performed univariate and multivariate analyses of prognostic factors that may affect overall survival (OS). Results In a study of 125 patients with advanced malignant melanoma, 53 patients participated, with a median follow‐up of 16 months. Among these, 69.8% died, and 30.2% remained on treatment. Median progression‐free survival (PFS) was 6 months, and median OS was 19 months. Patients treated with immune checkpoint inhibitors had improved outcomes, with a median PFS of 7 months and a median OS of 24 months. Patients with bone metastasis and aberrant Lactate dehydrogenase (LDH) post‐treatment had worse prognoses, while immunotherapy was a protective factor. Subgroup analysis showed the benefits of immunotherapy across various patient characteristics. No unexpected toxicities were observed. Conclusion The study highlights the efficacy of immune checkpoint inhibitors, particularly PD‐1 mAb, in improving survival outcomes for Chinese patients with metastatic melanoma.


INTRODUCTION
Currently, immune checkpoint inhibitors (ICI) have greatly improved the prognosis of advanced malignant melanoma.Immune checkpoint inhibitors, such as Ipilimumab, nivolumab, and pembrolizumab, have been successively approved by the US Food and Drug Administration for the treatment of advanced metastatic melanoma. 1,2Most of the current progression of immune checkpoint inhibitors for malignant melanoma is based on data from Caucasians in Western countries, but the benefit of Chinese patients is limited, mainly due to different pathological subtypes.[8] In a retrospective analysis, the objective response rate (ORR) of ipilimumab, pembrolizumab and pembrolizumab plus ipilimumab were 0%, 25% and 20%, respectively. 9In the KEYNOTE-151 study, the objective response rates in mucosal and acral melanoma of Chinese advanced melanoma patients were 13.3% for pembrolizumab and 15.8% (ORR), 10 respectively, median progression-free survival (PFS) 2.8 months, and median overall survival (OS) 12.1 months. 11Poor options for advanced malignant melanoma in China.Before 2017, the first-line treatment of advanced melanoma in China was dominated by dacarbazine-based chemotherapy.The median survival time of chemotherapy for patients with advanced melanoma is 6-9 months, with a 5-year survival rate of less than 10% 12 .
To determine whether immune checkpoint inhibitors can enhance the survival of Chinese patients with malignant melanoma, we conducted a retrospective analysis of 53 patients with metastatic melanoma treated at our hospital.This study aimed to assess the efficacy and safety of PD-1 mAb in Chinese patients with metastatic melanoma and perform univariate and multivariate analyses of potential prognostic factors impacting OS.

Patient population
We included patients aged at least 18 years, we enrolled patients who

Study design and follow-up
This study is a retrospective cohort study.Patients with locally advanced or metastatic malignant black melanoma treated in our department, were divided into immunotherapy group and nonimmunotherapy groups.Patient's clinical characteristics, treatment regimen, treatment lines, efficacy assessment, adverse reactions, disease progression, cause of death, were tracked and recorded until October 31, 2022 or until the death of the patient.Patients eligible for enrollment in this study, underwent a survival analysis.

Statistical analysis
PFS and OS were plotted using the Kaplan-Meier method, reporting the median and corresponding two-sided 95% CI, with a p-value < 0.05 considered statistically significant.PFS was defined as the time from PD-1, onset to disease progression or death (whichever comes first) as determined by RECIST 1.1.OS was defined as the time from the start of first-line treatment to death from any cause.The log-rank test was used to compare the correlation between baseline characteristics and OS.A Cox proportional hazards regression analysis was used to determine the relative impact of the identified prognostic factors.
The multiple cox regression analysis was performed using reverse stepwise (LR) for variables with p-value < 0.1 in univariate cox regression analysis.In the multivariate cox regression analysis, variables with a p-value < 0.05 were considered as independent prognostic factors for melanoma patients.

Patients and treatment
From January  targeted drugs, and 33 (62.3%) had received topical therapy.Baseline characteristics are shown in Table 1.
Forty-three patients were treated with immune checkpoint inhibitors, as compared with 10 patients (Table 2).Twelve patients in the immunotherapy group were on BRAF inhibitor and one patient in the no immunotherapy group was on BRAF inhibitor.More than half of the patients who had not been treated with immune checkpoint inhibitors did not undergo genetic testing.

Treatment-related toxicity
Of the 43 patients receiving immunotherapy, 21 had immune-related adverse effects, mostly grade 1-2, most commonly rash (8), hepatic insufficiency (5), and hypothyroidism (4).No other patients discontinued treatment due to immune-related adverse reactions, and no other new adverse reactions were observed.
For those patients treated with immune checkpoint inhibitors, the median PFS was 7 months, and the median PFS was 4 months without immunotherapy (p = 0.253, Table 3, Figure 1A).Patients receiving immune checkpoint inhibitors had a median OS of 24 months, and the median OS was 7 months (p = 0.001, Table 4, Figure 1B).Four (9.3%) of the patients receiving immune checkpoint inhibitors were still receiving PD-1 as of the time of publication.
This study also found that combined topical therapy showed a trend of survival benefit compared with no topical treatment.Local treatment included radiotherapy (23.43%), arterial perfusion therapy (16.30%), and ablation (7.13%).The median OS was 24 months versus 11 months for patients not (p = 0.327), as shown in Table 6.
Variables with a p value < 0.1 in univariant COX-regression analysis were selected for multivariant COX-regression analysis by the Backward Stepwise (LR).Variables with a p-value < 0.05 in multivariant COX-regression analysis were considered as independent prognostic factors for melanoma patients.
Each subgroup analysis also suggested that patients could benefit from immunotherapy regardless of age, BRAF V600E status, LDH, bone metastasis, and chemotherapy (Figure 2) Forest plot: subgroup analysis suggested that the prognosis factors affecting OS were performed in univariate analysis, and each subgroup could benefit from immunotherapy.OS, overall survival.

DISCUSSION
The pathological types and biological characteristics of melanoma in China are different from those in western countries.4][5] Immune checkpoint inhibitors have become the standard treatment regimen for advanced or metastatic cutaneous melanoma, however, there are limited data on acral and mucosal melanoma receiving immune checkpoint inhibitors, and they respond poorly to immunotherapy compared to the skin. 8,13A retrospective study, even in skin subtypes, anti-PD-1 mAbs were significantly less effective in Asians than in Caucasian. 14How to improve the prognosis of Asian patients with malignant melanoma is an urgent problem for us to solve.
This study included patients with acro and mucosal malignant melanoma, 26 acromalignant melanoma (49.1% of the total) and 17 mucosal malignant melanoma (32.1% of the total).The PD-1 mAb was well tolerated by the treated patients, with a median PFS of 7 months and a median OS of 24 months.These data support that PD-1 mAb can improve survival in Chinese patients with advanced or metastatic melanoma.However, the multivariate analysis results of this study also suggested that immunotherapy is a protective factor for OS, which also confirmed this view.It is worth mentioning that immune combination therapy accounted for 81.4% in this study, including combination chemotherapy and targeted drug therapy.Chemotherapy and antiangiogenesis-targeted therapy may promote the response to immunotherapy.
Chemotherapy has been the main treatment of advanced malignant melanoma, including dacarbazine, temozolomide, albumin-bound paclitaxel, and so forth.Dacarbazine was approved by the FDA as a standard chemotherapy regimen for melanoma treatment starting in 1975.Tmozolomide was similar to dacarbazine.A randomized phase III trial of temozolomide and dacarbazine in patients with metastatic melanoma showed that median OS was comparable (7.7 months for temozolomide and 6.4 months for dacarbazine, p = 0.20) and similar response rates between them (temozolomide was 13.5%, dacarbazine was 12.1%). 15A phase III randomized controlled clinical trial of albumin-bound paclitaxel and dacarbazine in first-line treatment of metastatic melanoma suggested a median PFS of 4.8 months for albumin-bound paclitaxel, 2.5 months (p = 0.044), median OS of 12.6 months for albumin-bound paclitaxel, 10.5 months (p = 0.271), and overall remission rates of albumin-bound paclitaxine, 15% and 11% (p = 0.239). 16These results suggest that chemotherapy has some activity on the treatment of advanced malignant melanoma but has limited impact on survival.The median OS of patients receiving chemotherapy in this study was significantly shorter compared to patients not receiving chemotherapy (14 months vs. 35 months, p = 0, Table 9), and the univariate analysis also suggested that chemotherapy was one of the adverse prognosis factors for OS (p < 0.1, Table 7).No conversion survival benefit from chemotherapy may be related to its chemotherapy toxicity, including myelosuppression, nausea and vomiting, increased toxic and side effects, decreased quality of life, and no improvement in OS rate.
In this study, 18 patients had combined immunotherapy or sequen- Abbreviations: IO, immuno-oncology, HR, hazard ratio, ECOG, eastern cooperative oncology group; LDH, lactate, dehydrogenase, MET, metastasis, LN MET, lymph node metastasis, CKIT, a gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, also known as CD117, NRAS, neuroblastoma RAS viral oncogene, that encodes an enzyme also called as NRAS enzyme, and MDM2, a gene that encodes a protein called as mouse double minute 2 homolog (MDM2).
tial chemotherapy (41.9% of the total population), which may be responsible for the longer OS than previous reports.
In this study, there were 17 immune combination targeted therapy (39.5% of the total population).Although targeted therapy was not a protective factor for OS in multivariate analysis, immune combination targeted therapy may be one of the reasons for prolonged OS of immune checkpoint inhibitors.This study had a limited number of samples and aimed to analyze the effect of immunotherapy on metastatic malignant black survival, and did not separately analyze BRAF and MEK inhibitors with anti-angiogenic targeted therapy.
Malignant melanoma with BRAF-V600 mutation, either targeted therapy after immunotherapy as recommended by NCCN guidelines, or immunization before targeted 19 as recommended by DREAMseq studies, suggests that BRAF-V600 mutant metastatic melanoma could benefit from immunotherapy.The subgroup analysis of this study also suggested that it could benefit from immunotherapy regardless of the The results showed that the response rate (RR) and disease control rate (DCR) of patients (7 acral melanoma, 4 mucosal melanoma) were 54.5% and 90.9%, respectively, no grade 3-4 adverse events or major complications were observed during the study period, and the median PFS was 10 months. 21Combined local therapy facilitates rapid tumor control, and combined immunotherapy facilitates prolonged survival.
We must admit that there are some limitations to our study.This was a retrospective study, which may cause some selection bias, in addition, we selected patients undergoing medication throughout in our department with a relatively small sample size.But our cohort also included some patients with poor medical condition and was more representative of the actual clinical situation.
In conclusion, immune checkpoint inhibitors can improve the prognosis of Chinese patients with malignant melanoma, and combination therapy will be a trend to improve the immune response and prolong survival, but which combination strategy will be the preferred regimen for Chinese patients with malignant melanoma still needs to be determined in more randomized clinical trials.More exploratory studies and establishing comprehensive treatment strategies are needed to improve the prognosis of Chinese melanoma patients.

were at least 18
years of age, with pathologically confirmed locally advanced or metastatic melanoma.Patients met the following inclusion criteria: (1) Patients must have at least one measurable lesion at baseline according to the Response Assessment criteria for solid tumors (RECIST version 1.1).(2) The Eastern Cooperative Oncology Group (ECOG) fitness status of 0 or 1, with adequate organ and bone marrow function.(3) Patients with an expected survival period of more than 3 months.(4) Patients who have received at least 1 cycle of first-line anti-tumor therapy before December 31, 2021.(5) Patients receiving full drug treatment in our department.Patients with an autoimmune disease were excluded.

F I G U R E 1
Progression-free survival and OS.Kaplan-Meier survival curves for progression-free survival between patients with or without IO (A) and overall survival (B) between patients with or without IO.OS, overall survival.
Demographics of study participants.
TA B L E 1 Progression free survival comparison between patients with or without IO (date from first line to date of PD).Data of patients who received IO therapy.Overall survival comparison between patients with or without localized therapy (date from first line to date of events).Univariant analysis of OS.Overall survival comparison between patients with or without chemo (date from first line to date of events).
of survival benefit from no local treatment, with PD-1 arterial perfusion therapy (16 patients, 30%).A study of PD-1 in our department TA B L E 7